Rebec G V, Pierce R C
Department of Psychology, Indiana University, Bloomington 47405.
Prog Neurobiol. 1994 Aug;43(6):537-65. doi: 10.1016/0301-0082(94)90052-3.
Ascorbate is an antioxidant vitamin that the brain accumulates from the blood supply and maintains at a relatively high concentration under widely varying conditions. Although neurons are known to use this vitamin in many different chemical and enzymatic reactions, only recently has sufficient evidence emerged to suggest a role for ascorbate in interneuronal communication. Ascorbate is released from glutamatergic neurons as part of the glutamate reuptake process, in which the high-affinity glutamate transporter exchanges ascorbate for glutamate. This heteroexchange process, which also may occur in glial cells, ensures a relatively high level of extracellular ascorbate in many forebrain regions. Ascorbate release is regulated, at least in part, by dopaminergic mechanisms, which appear to involve both the D1 and D2 family of dopamine receptors. Thus, amphetamine, GBR-12909, apomorphine, and the combined administration of D1 and D2 agonists all facilitate ascorbate release from glutamatergic terminals in the neostriatum, and this effect is blocked by dopamine receptor antagonists. Even though the neostriatum itself contains a high concentration of dopamine receptors, the critical site for dopamine-mediated ascorbate release in the neostriatum is the substantia nigra. Intranigral dopamine regulates the activity of nigrothalamic efferents, which in turn regulate thalamocortical fibers and eventually the glutamatergic corticoneostriatal pathway. In addition, neostriatonigral fibers project to nigrothalamic efferents, completing a complex multisynaptic loop that plays a major role in neostriatal ascorbate release. Although extracellular ascorbate appears to modulate the synaptic action of dopamine, the mechanisms underlying this effect are unclear. Evidence from receptor binding studies suggests that ascorbate alters dopamine receptors either as an allosteric inhibitor or as an inducer of iron-dependent lipid peroxidation. The applicability of these studies to dopamine receptor function, however, remains to be established in view of reports that ascorbate can protect against lipid peroxidation in vivo. Nevertheless, ample behavioral evidence supports an antidopaminergic action of ascorbate. Systemic, intraventricular, or intraneostriatal ascorbate administration, for example, attenuates the behavioral effects of amphetamine and potentiates the behavioral response to haloperidol. Some of these behavioral effects, however, may be dose-dependent in that treatment with relatively low doses of ascorbate has been reported to enhance dopamine-mediated behaviors. Ascorbate also appears to modulate glutamatergic transmission in the neostriatum. In fact, by facilitating glutamate release, ascorbate may indirectly oppose the action of dopamine, though the nature of the neostriatal dopaminergic-glutamatergic interaction is far from settled. Ascorbate also may alter the redox state of the NMDA glutamate receptor thus block NMDA-gated channel function.(ABSTRACT TRUNCATED AT 400 WORDS)
抗坏血酸是一种抗氧化维生素，大脑从血液供应中积累这种维生素，并在广泛变化的条件下将其维持在相对较高的浓度。尽管已知神经元在许多不同的化学和酶促反应中使用这种维生素，但直到最近才有足够的证据表明抗坏血酸在神经元间通讯中发挥作用。抗坏血酸作为谷氨酸再摄取过程的一部分从谷氨酸能神经元释放，在这个过程中，高亲和力的谷氨酸转运体用抗坏血酸交换谷氨酸。这种异质交换过程也可能发生在神经胶质细胞中，确保许多前脑区域细胞外抗坏血酸水平相对较高。抗坏血酸的释放至少部分受多巴胺能机制调节，这似乎涉及多巴胺受体的D1和D2家族。因此，苯丙胺、GBR - 12909、阿扑吗啡以及D1和D2激动剂的联合给药都促进新纹状体中谷氨酸能终末释放抗坏血酸，并且这种作用被多巴胺受体拮抗剂阻断。尽管新纹状体本身含有高浓度的多巴胺受体，但新纹状体中多巴胺介导的抗坏血酸释放的关键部位是黑质。黑质内的多巴胺调节黑质丘脑传出纤维的活动，进而调节丘脑皮质纤维，最终调节谷氨酸能皮质新纹状体通路。此外，新纹状体黑质纤维投射到黑质丘脑传出纤维，形成一个复杂的多突触回路，在新纹状体抗坏血酸释放中起主要作用。尽管细胞外抗坏血酸似乎调节多巴胺的突触作用，但其潜在机制尚不清楚。受体结合研究的证据表明，抗坏血酸要么作为变构抑制剂，要么作为铁依赖性脂质过氧化的诱导剂改变多巴胺受体。然而，鉴于有报道称抗坏血酸可以在体内防止脂质过氧化，这些研究对多巴胺受体功能的适用性仍有待确定。尽管如此，大量行为学证据支持抗坏血酸的抗多巴胺能作用。例如，全身、脑室内或新纹状体内给予抗坏血酸可减弱苯丙胺的行为效应，并增强对氟哌啶醇的行为反应。然而，其中一些行为效应可能是剂量依赖性的，因为据报道用相对低剂量的抗坏血酸治疗可增强多巴胺介导的行为。抗坏血酸似乎还调节新纹状体中的谷氨酸能传递。事实上，通过促进谷氨酸释放，抗坏血酸可能间接对抗多巴胺的作用，尽管新纹状体中多巴胺能 - 谷氨酸能相互作用的本质远未明确。抗坏血酸还可能改变NMDA谷氨酸受体的氧化还原状态，从而阻断NMDA门控通道功能。（摘要截断于400字）
